Thienyl, thienyloxy or furyl substituted prostaglandin derivatives in the 6-keto-PGE1 series

ABSTRACT

The invention relates to new prostaglandin derivatives of the 6-keto-PGE 1  series, to processes and intermediates for their manufacture and to their use as medicaments.

Prostaglandins are a group of fatty acids which are found in numeroustissues and organs of humans and animals. The skeleton of the naturallyoccurring prostaglandins consists of 20 carbon atoms which are arrangedin the form of a five-membered ring and two adjacent linear side chains.

The pharmacological effects of the prostaglandins extend, inter alia,into the fields of reproduction, the bronchial muscle tone, the bloodpressure and gastroenterology. The pharmacological characteristics ofthe naturally occurring prostaglandins are the subject of numerousreview articles, for example by N. H. Andersen and P. W. Ramwell inArch. Internal Med. 133, 30 (1974); R. L. Jones in Pathobiology Ann.1972, 359; J. Pike in Scient. American 225, 84 (1971) or M. P. L. Catonin Progress in Med. Chem. Volume 7, ed.: Butterworth, London 1971.

The synthesis of analogs of prostanoic acids, which are not naturallyoccurring and in which the large number of pharmacological effects ofthe naturally occurring prostaglandins are differentiated, is becomingincreasingly important.

The present invention relates to new compounds of the formula I ##STR1##which are structurally related to the naturally occurring prostaglandinsand in which R¹ denotes hydrogen or a straight-chain or branched alkylradical with up to 6 carbon atoms or a straight-chain or branchedunsaturated aliphatic hydrocarbon radical with up to 6 carbon atoms or acycloaliphatic hydrocarbon radical with 3 to 7 carbon atoms or anaraliphatic hydrocarbon radical with 7 to 9 carbon atoms or aphysiologically acceptable metal ion, NH₄ ion or ammonium ion derivedfrom a primary, secondary or tertiary amine, or a tetraalkylammonium ionand R² denotes (a) a cycloalkyl radical with 3 to 7 carbon atoms or (b)a straight-chain or branched alkyl radical with up to 8 carbon atoms, inwhich a CH₂ group which is not a terminal group can be replaced by anoxygen atom, or which alkyl radical can be substituted (b₁) by halogenor by an α- or β-thienyl or-furyl radical, which, in turn, can bemonosubstituted to trisubstituted in the nucleus by halogen,trifluoromethyl and/or alkyl or alkoxy, each with 1-6 C atoms, or (b₂)by a phenoxy radical, an α-or β-thienyloxy radical or a cycloalkoxyradical with 3 to 7 carbon atoms, it being possible for the saidradicals, in turn, to be monosubstituted to trisubstituted in thenucleus by halogen, trifluoromethyl and/or alkyl or alkoxy, each with1-6 C atoms.

Amongst the substituents mentioned for R¹, the following are preferred:hydrogen, a straight-chain or branched alkyl radical with up to 8 Catoms, a straight-chain or branched unsaturated aliphatic hydrocarbonradical with up to 4 C atoms, a cycloaliphatic hydrocarbon radical with5-7 C atoms and an araliphatic hydrocarbon radical with 7 to 8 C atoms.

Particularly preferred substituents are: hydrogen, methyl, ethyl,n-butyl, n-pentyl, n-hexyl, n-heptyl, 2-propyl, 2-butyl, 2-pentyl,3-hexyl, 2-methylpropyl, 2-methylbutyl, 4,4-dimethylpentyl,5,5-dimethylhexyl, cyclopentyl, cyclohexyl and cycloheptyl.

Amongst the substituents mentioned for R², the following are preferred:cycloalkyl with 5 to 7 C atoms, straight-chain alkyl radicals with 3 to7 C atoms, branched alkyl radicals with up to 8 C atoms, in which a CH₂group which is not a terminal group can be replaced by an oxygen atom,and straight-chain or branched alkyl radicals with up to 5 C atoms,which are substituted by halogen, thienyl, furyl, chlorothienyl,phenoxy, chlorophenoxy, thienyloxy, chlorothienyloxy or cyclohexyloxy.

Particularly preferred substituents are: 1,1-dimethyl-2-butoxy-ethyl,1,1-dimethyl-pentyl, n-propyl, 2-propyl, n-butyl, 2-butyl, t-butyl,n-pentyl, 3-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-ethylbutyl,2,2-dimethylbutyl, n-heptyl, 1,1-dimethyl-2-ethoxy-ethyl,1,1-dimethyl-2-methoxy-ethyl, 1,1-dimethyl-cyclohexyloxymethyl,1-fluoropentyl, 1-chloropentyl, 5-fluoropentyl, 5-chloropentyl,3-thienyl-2-ethyl, 2-thienyl-2-ethyl, 3-(2-chloro-thienyl)-2-ethyl,2-(5-chloro-thienyl)-2-ethyl, phenoxymethyl, 3-chloro-phenoxymethyl,2-thienyl-oxymethyl, 3-(2-chlorothienyl)-oxymethyl,2-(5-chlorothienyl)-oxymethyl, 3-furyl-2-ethyl, 2-furyl-2-ethyl,cyclopentyl, cyclohexyl and cycloheptyl.

The invention also relates to a process for the manufacture of compoundsof the formula I, which comprises (a) eliminating HX, with the aid of abase, from a compound of the formula II ##STR2## in which R¹ and R² havethe meaning indicated under formula I, R³ denotes an easily detachableprotective group and X denotes a halogen atom, a compound of the formulaIII ##STR3## being obtained, in which R¹ and R² have the meaningindicated under formula I and R³ denotes an easily detachable protectivegroup, (b) subjecting a compound of the formula III to acid hydrolysisto give a compound of the formula IV ##STR4## in which R¹ and R² havethe meaning indicated under formula I and R³ denotes an easilydetachable protective group, (c) converting a compound of the formula IVby oxidation to a compound of the formula V ##STR5## in which R¹ and R²have the meaning indicated under formula I and R³ denotes an easilydetachable protective group, (d) detaching the protective groups R³ froma compound of the formula V under suitable neutral or acid conditions, acompound of the formula I in which R¹ and R² have the meaning indicatedunder formula I being formed, and (e) if desired, converting a compoundof the formula I in which R¹ does not represent hydrogen or a cation byacid or alkaline hydrolysis to a compound of the formula I in which R¹denotes hydrogen or a physiologically acceptable cation; and (f) ifdesired, in a compound of the formula I in which R¹ denotes aphysiologically acceptable metal ion, NH₄ ion or ammonium ion, derivedfrom a primary, secondary or tertiary amine, or a tetraalkylammoniumion, replacing the cation R¹ by another cation.

The procedures used to manufacture the prostaglandin derivatives of theformula II used as the starting material in the process according to theinvention can be analogous to the processes which are described, forexample, in German Offenlegungsschrift No. 2,811,950.

The elimination of HX, where X preferably denotes bromine or iodine,from compounds of the formula II with the formation of compounds of theformula III proceeds under the action of bases in the presence orabsence of a solvent.

Bases which can be used are both inorganic and organic bases, such as,for example, alkali metal hydroxides or alkali metal carbonates,alcoholates, such as, for example, sodium methylate or potassiumtertiary butylate, amines, such as, for example, triethylamine,4-dimethylaminopyridine, dicyclohexylethylamine or1,4-diazabicyclo[2.2.2]octane, or amidines, such as, for example,1,5-diazabicyclo[3.4.0]non-5-ene (DEN) or1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The hydrolysis of compounds ofthe formula III to compounds of the formula IV is carried out by acidcatalysis at temperatures between -10° C. and +20° C., appropriately inan alcoholic or aqueous organic solvent. Suitable acids are dilutemineral acids or organic acids such as p-toluenesulfonic acid, oxalicacid or acetic acid.

The compounds of the formula IV are converted to compounds of theformula V by oxidation. Suitable oxidizing agents are, in particular,chromic acid, chromic acid/pyridine complexes, Jones reagent andpyridinium chlorochromate. Suitable solvents are those which cannot beoxidized themselves, such as, for example, acetone, ether and methylchloride.

The compounds of the formula V in which --COOR¹ represents an estergroup are converted to compounds of the formula I in which --COOR¹represents an ester group by removing the protective groups R³ in thepresence of dilute mineral acid or organic acids such asp-toluene-sulfonic acid, oxalic acid or acetic acid, appropriately in anaqueous/organic solvent, such as, for example, tetrahydrofuran/water.

Compounds of the formula I in which R¹ denotes an alkyl radical can besaponified in a conventional manner in an alkaline medium to givecompounds of the formula I in which R¹ denotes hydrogen or preferably acation, for example using NaOH or KOH in a low-molecular alcohol, suchas methanol, or ether, such as dimethoxyethane or THF, optionally in thepresence of water. Advantageously, the equimolar amount or a very slightexcess of alkali metal hydroxide is used, so that the alkali metal saltof the formula I (R¹ =alkali metal ion) is obtained by evaporating thesolvent.

The alkali metal cation can be replaced by any desired cations on ionexchangers in a conventional manner. For this purpose, the solution ofthe alkali metal salt of a compound of the formula I is allowed to runthrough a column filled with a cation exchanger, such as, for example,®Amberlite CG - 50 or ®Dowex CCR - 2.

The cation exchanger is charged with the desired cation, for examplewith an ammonium ion which is derived from a primary, secondary ortertiary amine. The desired salt is obtained by evaporating the eluate.The compounds of the formula II, III, IV and V can be employed for thesubsequent reactions in the form of a mixture of diastereomers withrespect to the position of the hydroxyl group on carbon atom 15(prostaglandin nomenclature), in the form of pure α- or β-isomers or inthe form of optically active antipodes. The separation of stereoisomersor the resolution of antipodes can, however, also be effected after anysubsequent reaction stage. This means that all the reactions describedcan be carried out with mixtures of diastereomers, with purediastereomers or with optically active antipodes.

If the individual reaction products are not obtained in a form which isalready sufficiently pure for them to be employed for the subsequentreaction step, purification by means of, for example, columnchromatography, thin layer chromatography or high-pressure liquidchromatography is advisable.

In addition to the compounds named in the examples, the followingcompounds in particular can also be manufactured by the processesaccording to the invention: 16-chloro-6-keto-PGE₁ methyl ester,16-chloro-6-keto-PGE₁, 16-fluoro-6-keto-PGE₁ ethyl ester,17-(2-thienyl)-18, 19, 20-trinor-6-keto-PGE₁,17-(3-(2-chlorothienyl)-18, 19, 20-trinor-6-keto-PGE₁ methyl ester,16-phenoxy-17, 18, 19, 20-tetranor-6-keto-PGE₁ ethyl ester,16-(3-trifluoromethyl-phenoxy)-17, 18, 19, 20-tetranor-6-keto-PGE₁n-butyl ester, 16-(3-(2-chloro)-thienyloxy)-17, 18, 19,20-tetranor-6-keto-PGE₁ methyl ester, 16-(2-thienyloxy)-17, 18, 19,20-tetranor-6-keto-PGE₁ methyl ester, 17-(3-furyl)-18, 19,20-trinor-6-keto-PGE₁, 15-cyclopentyl-16, 17, 18, 19,20-pentanor-6-keto-PGE₁ propyl ester, 15-cyclopentyl-16, 17, 18, 19,20-pentanor-6-keto-PGE₁, 17-oxa-6-keto-PGE₁ methyl ester, 16,16-dimethyl-17-oxa-21-homo-6-keto-PGE₁, 17-oxa-16, 16,19-trimethyl-6-keto-PGE₁ n-butyl ester, 16, 16-dimethyl-18-oxa-21-homo-6-keto-PGE₁, 19-oxa-6-keto-PGE₁ ethyl ester, 16,16-diethyl-19-oxa-6-keto-PGE₁ methyl ester, 19-oxa-16, 16, 20,20-tetramethyl-6-keto-PGE₁ isopropyl ester, 18,18-dimethyl-19-oxa-6-keto-PGE₁ and 16,16-dimethyl-20-oxa-21-homo-6-keto-PGE₁ methyl ester.

The compounds of the formula I are distinguished by an inhibitory actionon thrombocyte aggregation, relaxation of the vascular wall, especiallyof the coronary arteries, and hypotensive properties.

They can therefore be used as medicaments. The compounds of the formulaI are used as hypotensive agents in a daily dosage range of 0.001 mg-0.1mg/kg and preferably 0.005 mg-0.1 mg/kg in the case of intravenousadministration and in a daily dosage range of 0.001 mg-1 mg/kg andpreferably 0.05-1 mg/kg in the case of oral administration. Proper unitdosages amount to about one third of the mentioned daily dosages. Forrelaxation of the vascular wal, especially of the coronary arteries, andfor inhibition of thrombocyte aggregation, dosages lower than thoseindicated above are also effective in some cases.

The compounds, according to the invention, of the formula I can be usedin the form of the free acids or in the form of their physiologicallyacceptable inorganic or organic salts or in the form of esters. Acidsand salts or esters can be used in the form of their aqueous solutionsor suspensions or also as solutions or suspensions in pharmacologicallyacceptable organic solvents, such as monohydric or polyhydric alcohols,such as, for example, ethanol, ethylene glycol or glycerol, oils, suchas, for example, sunflower oil or cod-liver oil, ethers, such as, forexample, diethylene glycol dimethyl ether, or also polyethers, such as,for example, polyethylene glycol, or in the presence of otherpharmacologically acceptable polymeric carriers, such as, for example,polyvinylpyrrolidone.

Formulations which can be used are the customary galenical infusion orinjection solutions and tablets, and also formulations for localapplication, such as creams, emulsions, suppositories or aerosols.

A further use of the new compounds lies in the combination with otheractive compounds. In addition to other suitable substances, theseinclude, in particular: circulatory preparations in the broadest sense,such as, for example, cardiac glycosides, such as digitoxin,sympathomimetic agents, such as Suprifen, β-sympatholytic agents, suchas Inderal, coronary dilators, such as chromonar or prenylamine,hypotensive substances, such as reserpine or clonidine, antiarrhythmicagents, substances which stimulate the blood flow, anticoagulants orfibrinolytic agents, diuretic agents, such as, for example, furosemide,substances which lower the lipid level, prostaglandins or prostaglandinantagonists or prostaglandin biosynthesis inhibitors, such as, forexample, non-steroid antiphlogistic agents, thromboxane synthetaseinhibitors, psychopharmaceuticals and vitamins.

The compounds of the formula II, III, IV and V are new, valuableintermediates for the manufacture of compounds of the formula I.

EXAMPLE 1 (a)5-Iodo-16-(3-thienyloxy)-11,15-bis-tetrahydropyranyloxy-17,18,19,20-tetranor-PGI₁methyl ester II

450 mg (0.84 mmole) of5-iodo-16-(3-thienyloxy)-17,18,19,20-tetranor-PGI₁ methyl ester(prepared analogously to DE-OS No. 2,811,950) are dissolved in 6 ml ofabsolute methylene chloride.

84×5=420 mg (5 mmoles) of distilled dihydropyran and also a smallspatula tip (about 5 mg) of p-toluenesulfonic acid are then added andthe reaction mixture is stirred for 1 hour at room temperature. Afterthe reaction has ended, the methylene chloride phase is washed withsaturated NaHCO₃ solution until acid-free, dried over magnesium sulfateand filtered and the filtrate is concentrated to dryness in vacuo.

Yield: 0.57 g of a pale yellow oil (II).

TLC_(in) ethyl acetate Rf=0.9.

Staining with molybdophosphoric acid.

Plate warmed to 100° C.

    ______________________________________                                        NMR: δ values                                                                     1.0-2.8  (m, 24H) --CH.sub.2 --, CH--                               in CDCl.sub.3                                                                           3.6      (s, 3H)  OCH.sub.3                                                   3.9      (d, 2H)  --CH.sub.2 --O--thiophen                                    4.5-4.7  (m, 3H)  --CHI--, --O--CH--O--                                       5.3-5.7  (m, 2H)  olefinic proton                                             6.15-7.3 (m, 3H)  thiophen                                          ______________________________________                                    

EXAMPLE 1 b5-Iodo-17-(3-thienyl)-11,15-bis-tetrahydropyranyloxy-18,19,20-trinor-PGI.sub.1methyl ester

Obtained from 5-iodo-17-(3-thienyl)-18,19,20-trinor-PGI₁ methyl ester byreaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                            1.1-2.9  (m, 26H) --CH.sub.2 --, >CH--                                        3.6      (s, 3H)  OCH.sub.3                                                   4.6-4.8  (m, 3H)  --O--CH--O--,                                                                 --CH--I                                                     3.5-4.2  (m, 3H)  --CH--OTHP,                                                                   --CH--O--                                                   5.4-5.6  (m, 2H)  olefinic protons                                            6.8-7.25 (m, 3H)  thiophen                                      ______________________________________                                    

EXAMPLE 1 c5-Iodo-16,16-dimethyl-18-oxa-11,15-bis-tetrahydropyranyloxy-PGI₁ methylester

Obtained from 5-iodo-16,16-dimethyl-18-oxa-PGI₁ methyl ester, byreaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                            0.9     (d, 6H)  --C(CH.sub.3).sub.2                                          1.1     (t, 3H)  CH.sub.3                                                     1.2-2.7 (m, 24H) --CH.sub.2 --, --CH<                                         3.2     (s, 2H)  --OCH.sub.2 --C(CH.sub.3).sub.2                              3.4     (q, 2H)  --OCH.sub.2 --CH.sub.3                                       3.6     (s, 3H)  OCH.sub.3                                                    3.1-4.1 (m, 6H)  --CH.sub.2 --O--, --CHO--                                    4.3-4.7 (m, 3H)  CH--I, --O--CH--O--                                          5.3-5.6 (m, 2H)  olefinic protons                               ______________________________________                                    

EXAMPLE 1 d5-Iodo-16,16-dimethyl-18-oxa-11,15-bis-tetrahydropyranyloxy-20-nor-PGI.sub.1methyl ester

Obtained from 5-iodo-16,16-dimethyl-18-oxa-20-nor-PGI₁ methyl ester, byreaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                             0.9     (d, 6H)  --C(CH.sub.3).sub.2                                          1.1-2.6 (m, 24H) --CH.sub.2 --, >CH--                                         3.25    (s, 3H)  --OCH.sub.3                                                  3.6     (s, 3H)  --COOCH.sub.3                                                3.1-4.1 (m, 10H) --OCH.sub.2 --,                                                               --OCH--                                                      4.2-4.7 (m, 3H)  --O--CH--O--,                                                                 --CH--I                                                      5.3-5.6 (m, 2H)  olefinic protons                              ______________________________________                                    

EXAMPLE 1 e5-Iodo-16,16-dimethyl-18-oxa-11,15-bis-tetrahydropyranyloxy-20-homo-PGI.sub.1methyl ester

Obtained from 5-iodo-16,16-dimethyl-18-oxa-20-homo-PGI₁ methyl ester, byreaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                            0.9     (d + t, 9H)                                                                             --C(CH.sub.3).sub.2,                                                          --CH.sub.2 CH.sub.2--CH.sub.3                               1.1-2.6 (m, 24H)  --CH.sub.2 --, >CH--                                        3.6     (s, 3H)   --OCH.sub.3                                                 3.0-4.1 (m, 12H)  --OCH.sub.2,                                                                  --OCH--                                                     4.2-4.7 (m, 3H)   --O--CH--O--,                                                                 --CH--I                                                     5.3-5.6 (m, 2H)   olefinic protons                              ______________________________________                                    

EXAMPLE 1 f 5-Iodo-16,16-dimethyl-11,15-bis-tetrahydropyranyloxy-PGI₁methyl ester

Obtained from 5-iodo-16,16-dimethyl-PGI₁ methyl ester, by reactionanalogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                            0.9     (t + d, 9H)                                                                             --C(CH.sub.3).sub.2,                                                          CH.sub.3 --                                                 1.0-2.6 (m, 30H)  --CH.sub.2 --, >CH--                                        3.6     (s, 3H)   --OCH.sub.3                                                 3.2-4.2 (m, 7H)   --CH.sub.2 O--,                                                               --CHO--                                                     4.2-4.7 (m, 3H)   --O--CH--O--,                                                                 --CH--I                                                     5.3-5.6 (m, 2H)   olefinic protons                              ______________________________________                                    

EXAMPLE 1 g 5-Iodo-16-fluoro-11,15-bis-tetrahydropyranyloxy-PGI₁ methylester

Obtained from 5-iodo-16-fluoro-PGI₁ methyl ester, by reaction analogousto Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                            3.6      (s, 3H)   --COOCH.sub.3                                              5.35-5.65                                                                              (m, 2H)   olefinic protons                             ______________________________________                                    

EXAMPLE 1 h5-Iodo-17-phenoxy-11,15-bis-tetrahydropyranyloxy-18,19,20-trinor-PGI₁methyl ester

Obtained from 5-iodo-17-phenoxy-18,19,20-trinor-PGI₁ methyl ester byreaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3): δ values:                                                           3.6     (s, 3H)   COOCH.sub.3                                                 5.3-5.6 (m, 2H)   olefinic protons                                            6.8-7.3 (m, 5H)   aromatic protons                              ______________________________________                                    

EXAMPLE 1 i5-Iodo-16,16-dimethyl-16-(cyclohexyloxy)-11,15-bis-tetrahydropyranyloxy-17,18,19,20-tetranor-PGI₁methyl ester

Obtained from5-iodo-16,16-dimethyl-16-(cyclohexyloxy)-17,18,19,20-tetranor-PGI₁methyl ester by reaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values:                                                            1.0     (d, 6H)   C(CH.sub.3).sub.2                                           0.9-3.0 (m, 33H)  CH.sub.2, >CH--                                             3.6     (s, 3H)   --COCH.sub.3                                                5.3-5.6 (m, 2H)   olefinic protons                              ______________________________________                                    

EXAMPLE 1 j5-Iodo-15-cyclohexyl-11,15-bis-tetrahydropyranyloxy-16,17,18,19,20-pentanor-PGI₁methyl ester

Obtained from 5-iodo-15-cyclohexyl-16,17,18,19,20-pentanor-PGI₁ methylester by reaction analogous to Example 1 a.

    ______________________________________                                        NMR (CDCl.sub.3) δ values                                                             3.6     (s, 3H)   --COOCH.sub.3                                               5.3-5.5 (m, 2H)   olefinic protons                              ______________________________________                                    

EXAMPLE 216-(3-Thienyloxy)-11,15-bis-tetrahydropyranyloxy-17,18,19,20-tetranor-PGI.sub.2methyl ester III

0.57 g (1 mmole) of5-iodo-16-(3-thienyloxy)-11,15-bis-tetrahydropyranyloxy-17,18,19,20-tetranor-PGI₁methyl ester (Example 1a) are dissolved in 4.0 ml of1,5-diazabicyclo[5.4.0]undec-5-ene with vigorous stirring. The solutionis warmed at 70°-75° C. for about 1.5 hours. After the reaction hasended, the reaction mixture is taken up in 50 ml of ethyl acetate+30 mlof water. The organic phase is separated off and dried over MgSO₄, themixture is filtered and the solvent is removed from the filtrate invacuo; a pale yellow oil is obtained as the residue and this can be usedfurther without further purification.

Yield: 0.49 g of (III).

    ______________________________________                                        TLC in ethyl acetate/AcOH R.sub.f = 0.93                                      97.5                  2.5                                                     ______________________________________                                    

Staining with molybdophosphoric acid, plates warmed to 100° C.

EXAMPLE 2 b to 2 j

Analogously to Example 2 a, compounds 2 b to 2 j (formula III), R¹ =CH₃,can be prepared from the compounds of Examples 1 b to 1j, by theelimination of HI.

    __________________________________________________________________________                              Rf values                                                                     glacial acetic acid/                                                          ethyl acetate =                                     Example 2                                                                           R.sup.2             2.5/97.5                                            __________________________________________________________________________    (a)                                                                                  ##STR6##           0.93                                                (b)                                                                                  ##STR7##           0.87                                                (c)                                                                                  ##STR8##           (cyclohexane 2) 0.63 (ethyl acetate 1)              (d)                                                                                  ##STR9##           0.95                                                (e)                                                                                  ##STR10##          0.91                                                (f)                                                                                  ##STR11##          0.94                                                (g)                                                                                  ##STR12##                                                              (h)                                                                                  ##STR13##                                                              (i)                                                                                  ##STR14##                                                              (j)                                                                                  ##STR15##                                                              __________________________________________________________________________

EXAMPLE 3 a6-Keto-11,15-bis-tetrahydropyranyloxy-16-(3-thienyloxy)-17,18,19,20-tetranor-PGF₁methyl ester IV

0.49 g of16-(3-thienyloxy)-11,15-bis-tetrahydropyranyloxy-17,18,19,20-tetranor-PGI.sub.2methyl ester (Example 2 a) are dissolved in 30 ml of ethyl acetate and 8ml of 2 N aqueous hydrochloric acid are added and the resulting mixtureis stirred at room temperature for about 15 minutes. The organic phaseis again separated off, dried over MgSO₄, filtered and concentrated invacuo.

Yield: 0.47 g of a pale oil IV.

    ______________________________________                                        TLC ethyl acetate/AcOH R.sub.f = 0.78                                                             (molybdophosphoric acid,                                  97.5    2.5         plate warmed to 100° C.)                           NMR: δ                                                                  values                                                                        in CDCl.sub.3                                                                         1.1-2.7  (m, 26H) --CH.sub.2 --, >CH--                                        3.6      (s, 3H)  OCH.sub.3                                                   3.1-4.1  (m, 12H) --CH--O--THP, --CH.sub.2 --O--,                                               --OH                                                        4.3-4.9  (m, 2H)  --O--CH--O--                                                5.3-5.9  (m, 2H)  olefinic protons                                            6.1-7.3  (m, 3H)  thiophen                                            ______________________________________                                    

EXAMPLE 3 b to 3j

Analogously to Example 3 a, compounds 3 b to 3j (formula IV), R¹ =CH₃,can be prepared from the compounds of Examples 2 b to 2j by treatmentwith 2 N hydrochloric acid.

    __________________________________________________________________________                              R.sub.f values                                                                (glacial acetic acid/                                                         ethyl acetate =                                     Example 3                                                                           R.sup.2             2.5/97.5)                                           __________________________________________________________________________    (a)                                                                                  ##STR16##          0.78                                                (b)                                                                                  ##STR17##          0.73                                                (c)                                                                                  ##STR18##          (cyclohexane 2) 0.15 (ethyl acetate 1)              (d)                                                                                  ##STR19##          0.80                                                (e)                                                                                  ##STR20##          0.85                                                (f)                                                                                  ##STR21##          0.83                                                (g)                                                                                  ##STR22##                                                              (h)                                                                                  ##STR23##                                                              (i)                                                                                  ##STR24##                                                              (j)                                                                                  ##STR25##                                                              __________________________________________________________________________

EXAMPLE 4 a6-Keto-11,15-bis-tetrahydropyranyloxy-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁methyl ester V

0.4 g (0.7 mmole) of6-keto-11,15-bis-tetrahydropyranyloxy-16-(3-thienyloxy)-17,18,19,20-tetranor-PGF₁methyl ester (Example 3 a) is dissolved in 5 ml of acetone. 0.6 ml of"Jones" reagent (prepared from 1.05 g of chromium trioxide, 0.84 ml ofsulfuric acid and 2 ml of water) is added dropwise at -20° to -25° C.After 1/2 an hour the reaction has ended and 1 ml of isopropanol isallowed to run in dropwise. (Color change from yellow-orange to green).20 ml of NaCl solution and 50 ml of ethyl acetate are then added. Aftershaking, the ethyl acetate phase is washed with sodium bicarbonate untilacid-free. The organic phase is dried over magnesium sulfate andconcentrated in vacuo.

Yield: 0.38 g of a colorless oil.

TLC_(in) toluene/ethyl acetate, 1:1 R_(f) =0.38.

(Staining with molybdophosphoric acid, plate warmed to 100° C.).

EXAMPLE 4 b to 4j

Analogously to Example 4 a, compounds 4 b to 4 j (formula V), R¹ =CH₃,can be prepared from the compounds of Examples 3 b to 3 j by oxidationwith "Jones" reagent.

    __________________________________________________________________________    Example 4                                                                           R.sup.2             R.sub.f values                                      __________________________________________________________________________    (a)                                                                                  ##STR26##          (toluene 1) 0.38 (ethyl acetate 1)                  (b)                                                                                  ##STR27##          (cyclohexane 2) 0.26 (ethyl acetate 1)              (c)                                                                                  ##STR28##          (cyclohexane 1) 0.22 (ethyl acetate 1)              (d)                                                                                  ##STR29##          (cyclohexane 1) 0.19 (ethyl acetate 1)              (e)                                                                                  ##STR30##          (cyclohexane 1) 0.25 (ethyl acetate 1)              (f)                                                                                  ##STR31##          (cyclohexane 1) 0.23 (ethyl acetate 1)              (g)                                                                                  ##STR32##                                                              (h)                                                                                  ##STR33##                                                              (i)                                                                                  ##STR34##                                                              (j)                                                                                  ##STR35##                                                              __________________________________________________________________________

EXAMPLE 5 a 6-Keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ methylester I

280 mg (0.65 mmole) of6-keto-11,15-bis-tetrahydropyranyloxy-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁methyl ester (Example 4a) are dissolved in 4 ml of THF. After adding 10ml of 66% acetic acid, the reaction mixture is warmed at 50° C. for 2hours, with stirring. 60 ml of ethyl acetate are then added to thereaction mixture, and 30 ml of saturated NaCl solution are added. Aftershaking, the organic layer is separated off and washed with saturatedNaHCO₃ solution until acid-free. The aqueous phase is extracted twicemore with ethyl acetate. The organic phases are combined, dried overMgSO₄, filtered and concentrated in vacuo.

Yield: 193 mg of a yellow oil.

The substance is purified on a Merck size B prepacked column (SiO₂ -60).Eluant: 5/1 ethyl acetate/toluene.

Yield of pure product: 172 mg.

TLC_(ethyl) acetate R_(f) =0.15.

    ______________________________________                                        NMR δ values:                                                                     1.0-2.95 (m, 16H) --CH.sub.2 --, >CH--, --OH                        in CDCl.sub.3                                                                           3.6      (s, 3H)  --OCH.sub.3                                                 3.9      (d, 2H)  --CH.sub.2 O--thiophen                                      4.1-4.6  (m, 2H)  --CH--OH                                                    5.4-5.8  (m, 2H)  olefinic protons                                            6.1-7.3  (m, 3H)  thiophen                                          ______________________________________                                    

EXAMPLE 5 b to 5j

Analogously to Example 5 a, compounds 5 b to 5 j (formula I), R¹ =CH₃,can be prepared from the compounds of Examples 4 b to 4 j by detachingthe protective groups R³ using 66% strength acetic acid in THF.

    __________________________________________________________________________                              δ values                                      Example 5                                                                           R.sup.2             NMR (CDCl.sub.3)                                    __________________________________________________________________________    (a)                                                                                  ##STR36##          1.0-2.95 (m, 16H) CH.sub.2, >CH, OH; 3.6 (s,                                  3H) OCH.sub.3 ; 3.9 (d, 2H) CH.sub.2 Othiophen;                               4.1-4.6 (m, 2H) CHOH; 5.4-5.8 (m, 2H) olefinic                                protons, 6.1-7.3 (m, 3H) thiophen                   (b)                                                                                  ##STR37##          0.95-3.0 (m, 20H) CH.sub.2, >CH, OH; 3.6 (s,3H)                               CH.sub.3 ; 3.7-4.5 (m, 2H) CHOH; 5.3-5.9 (m,                                  2H) olefinic protons 6.8-7.3 (m, 3H) thiophen       (c)                                                                                  ##STR38##          0.9 (s, 6H) C(CH.sub.3).sub.2 ; 1.15 (t, 3H)                                  CH.sub.2 CH.sub.3 ; 1.4-2.95 (m, 14H) CH.sub.2                                >CH; 3.3 (s, 2H) OCH.sub.2; 3.5 (q, 2H)                                       OCH.sub.2 CH.sub.3 ; 3.6 (s, 3H) OCH.sub.3 ;                                  3.8-4.5 (m, 2H) CHOH; 5.5-5.8 (m, 2H) olefinic                                protons                                             (d)                                                                                  ##STR39##          0.9 (s, 6H) C(CH.sub.3).sub.2 ; 1.1-2.9 (m,                                   16H) CH.sub.2, >CH, OH; 3.2 (s, 2H) CH.sub.2                                  OCH.sub.3 ; 3.3 (s, 3H) CH.sub.2OCH.sub.3 ; 3.6                               (s, 3H) COOCH.sub.3 ; 3.7-4.5 (m,2H) CHOH;                                    5.5-5.8 (m, 2H) olefinic protons                    (e)                                                                                  ##STR40##          0.9 (s + t, 9H) C(CH.sub.3).sub.2, CH.sub.3 ;                                 1.2-2.9 (m, 16H) CH.sub.2, >CH; 3.25 (s, 2H)                                  CH.sub.2 O; 3.35 (t, 2H) OCH.sub.2 CH.sub.2                                   CH.sub. 3 ; 3.6 (s, 3H) COOCH.sub.3 ; 3.7-4.4                                 (m, 2H) CHOH; 5.5-5.7 (m, 2H) olefinic protons      (f)                                                                                  ##STR41##          0.9 (s + t,9H) (CH.sub.3), CH.sub.3 ; 3.6 (s,                                 3H) COOCH.sub.3 5.5-5.7 (m, 2H) olefinic                                      protons                                             (g)                                                                                  ##STR42##          0.95 (t, 3H) CH.sub.3, 3.6 (s, 3H)COOCH.sub.3                                 5.45-5.6 (m, 2H) olefinic protons                   (h)                                                                                  ##STR43##          3.85 (d, 2H) CH.sub.2OPh 3.6 (s, 3H)                                          COOCH.sub.3 5.5- 5.7 (m, 2H) olefinic protons                                 6.8-7.3 (m, 5H) aromatic protons                    (i)                                                                                  ##STR44##          1.05(d, 6H) C<(CH.sub.3).sub.2 ; 0.9-3.1 (m,                                  23H) CH.sub.2 , CH, OH; 3.6 (s, 3H) OCH.sub.3 ;                               .4-4.3 (m, 3H) CHOH, CHO; 5.5-5.75 (m, 2H)                                    olefinic protons                                    (j)                                                                                  ##STR45##          1.0-3.0 (m, 26H) CH.sub.2, CH, OH, 3.6 (s, 3H)                                COOCH.sub.3, 5.45-5.65 (m, 2H) olefinic             __________________________________________________________________________                              protons                                         

EXAMPLE 6 a 6-Keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ I

170 mg (0.4 mmole) of 6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁methyl ester (Example 5 a) are dissolved in 30 ml of 80% ethanol. Asolution of 67.5 mg of sodium in 4 ml of ethanol is added to thissolution, with stirring. The resulting mixture is stirred for 3 hours at35° under argon and acidified to pH 4 with 2 N citric acid solution,with ice-cooling, and the reaction mixture is extracted with ethylacetate, the organic phase is dried over MgSO₄ and filtered and thesolvent is removed in vacuo.

Yield: 150 mg of a brown oil.

Column chromatography on a Merck size A pre-packed column (SiO₂ -60)with ethyl acetate gives 95 mg of a colorless oil.

    ______________________________________                                        NMR:    1.0-2.9   (m, 15H)     --CH.sub.2, >CH--,                                     3.9       (d, 2H)      --CH.sub.2 O--thiophen                                 4.1-4.8   (m, 2H)      --CH--OH                                               4.9-5.2   (broad s, 3H)                                                                              OH, COOH                                               5.4-5.8   (m, 2H)      olefinic protons                                       6.1-7.3   (m, 3H)      thiophen                                       ______________________________________                                    

EXAMPLE 6 b to 6j

Analogously to Example 6 a, compounds 6 b to 6 j (formula I), R¹ =H, canbe prepared from the compounds 5 b to 5 j by ester saponification.

    ______________________________________                                        Example 6   R.sup.2                                                           ______________________________________                                        (a)                                                                                        ##STR46##                                                        (b)                                                                                        ##STR47##                                                        (c)                                                                                        ##STR48##                                                        (d)                                                                                        ##STR49##                                                        (e)                                                                                        ##STR50##                                                        (f)                                                                                        ##STR51##                                                        (g)                                                                                        ##STR52##                                                        (h)                                                                                        ##STR53##                                                        (i)                                                                                        ##STR54##                                                        (j)                                                                                        ##STR55##                                                        ______________________________________                                    

EXAMPLE 7 a The sodium salt of6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ I

170 mg (0.4 mmole) of 6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁methyl ester (Example 5 a ) are dissolved in 30 ml of 80% ethanol. Asolution of 67 mg of sodium in 4 ml of ethanol is added to thissolution, with stirring. The resulting mixture is stirred for 3 hours at35° C. under argon, the solution is filtered through active charcoal andthe solvent is removed in vacuo at -10° C. (freeze drying). The sodiumsalt of the prostaglandin derivative is obtained in the form of acolorless powder.

EXAMPLE 7 b The potassium salt of6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ I

192 mg of pure 6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ methylester (Example 5 a), 1.1 ml of 0.5 M potassium hydroxide solution and 2ml of methanol are allowed to stand at room temperature for 24 hoursunder an inert gas. The methanol is stripped off in vacuo and theaqueous solution of the potassium salt is freeze-dried. The potassiumsalt of the prostaglandin derivative is obtained in the form of acolorless powder.

EXAMPLE 7 c Triethylammonium salt of6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ I

An aqueous solution of 50 mg of the sodium salt of6-keto-16-(3-thienyloxy)-17,18,19,20-tetranor-PGE₁ (Example 7 a) isintroduced into a column containing 15 g of Amberlite CG - 50(triethylammonium form). The product is eluted with a 3% strengthaqueous solution of triethylammonium carbonate. On freeze-drying theeluate, the product is obtained in the form of a crystalline powder(decomposition >50° C.).

EXAMPLE 7 d

Analogously to Example 7 a to 7 c, the corresponding alkali metal saltsor ammonium salts of the compounds of Examples 6 a to 6 j can beprepared from the said compounds by alkaline ester saponification and,if necessary, chromatography on ion exchangers.

What is claimed is:
 1. A compound of the formula ##STR56## wherein R¹ ishydrogen, linear or branched alkyl having up to 8 carbon atoms, linearor branched unsaturated aliphatic hydrocarbon having 3 to 6 carbonatoms, cycloaliphatic hydrocarbon having 3 to 7 carbon atoms,araliphatic hydrocarbon having 7 to 9 carbon atoms, a physiologicallyacceptable metal ion, NH₄ ⁺ ion, an ammonium ion derived from a primary,secondary or tertiary amine or a tetraalkylammonium ion;R² is linear orbranched alkyl having up to 8 carbon atoms and substituted with α- orβ-thienyl, α- or β-thienyloxy, α- or β-furyl, or such thienyl,thienyloxy, or furyl mono-, di-, or tri-substituted in the nucleus withhalogen, trifluoromethyl, or alkyl or alkoxy each having 1 to 6 carbonatoms; and R³ is hydrogen or an easily-detachable protective group.
 2. Acompound as in claim 1 wherein R³ is an easily-detachable protectivegroup.
 3. A compound as in claim 1 wherein R³ is hydrogen.
 4. Apharmaceutical preparation for the treatment of thromboses, infarcts, orhypertension, which preparations comprise an effective amount of acompound as in claim 3 and a pharmaceutically acceptable carriertherefor.
 5. A method for treating thromboses, infarcts, or hypertensionin a patient suffering from one or more of the same, which methodcomprises orally, parenterally, or locally administering to said patientan effective amount of a compound as in claim 3.